The applicant is a physician scientist who has completed a neurology residency and a clinical epilepsy fellowship and is a recently appointed tenure-track Assistant Professor in the Vanderbilt University Neurology Department. The five year support from a Mentored Career Development Award (K08) would be used by the applicant to become established as an independent investigator working as a synaptic physiologist with the goal of understanding molecular mechanisms of epileptogenesis and neurodegeneration. This proposal focuses on understanding the role of the ubiquitin proteasome system (UPS) in regulating glutamatergic synaptic transmission, using the Drosophila neuromuscular junction (NMJ) and cultured hippocampal neurons as model synaptic systems. The covalent addition of the small protein, ubiquitin, targets proteins for intracellular trafficking and degradation by the proteasome. Recently, the UPS has been demonstrated to function locally at the synapse and regulate synaptic plasticity, but the mechanistic details about the specific ubiquitin ligases, protein targets, and the time scale over which the regulation occurs have just begun to be addressed. Preliminary data from the Drosophila NMJ suggests that the UPS regulates the abundance of the key postsynaptic density organizing protein, discs large, and also regulates a retrograde signaling pathway important for maintaining homeostatic synaptic plasticity. Understanding the mechanisms of UPS regulation of these fundamental synaptic pathways will likely have widespread implications for understanding the physiological changes in synaptic strength that occur during learning and memory as well as pathological changes that occur in epilepsy and neurodegenerative diseases. The proposed research will be performed under the guidance of Dr. Kendal Broadie, Stevenson Professor of Neurobiology, and Dr. Robert Macdonald, Chair of the Vanderbilt Neurology Department, who has a distinguished record of training physician scientists investigating basic mechanisms of epilepsy. Understanding the mechanisms of long-term synaptic changes that occur in epilepsy and neurodegenerative diseases is fundamental to developing new and better treatments for these diseases. Given the large complement of UPS regulatory proteins encoded in the genome, identifying specific synaptic UPS pathways offers the hope of developing targeted interventions for prevention and treatment of these diseases.